Pharmacokinetic profile of defibrotide in patients with renal impairment

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction),...

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Autores principales: Tocchetti, Paola, Tudone, Elena, Marier, Jean-Francois, Marbury, Thomas C, Zomorodi, Katie, Eller, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2016
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993270/
https://www.ncbi.nlm.nih.gov/pubmed/27574402
http://dx.doi.org/10.2147/DDDT.S112181
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author Tocchetti, Paola
Tudone, Elena
Marier, Jean-Francois
Marbury, Thomas C
Zomorodi, Katie
Eller, Mark
author_facet Tocchetti, Paola
Tudone, Elena
Marier, Jean-Francois
Marbury, Thomas C
Zomorodi, Katie
Eller, Mark
author_sort Tocchetti, Paola
collection PubMed
description Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (C(max)); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC(0–t)); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC(0–∞)). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC(0–t), 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; C(max), 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC(0–t), 117 µg·h/mL; AUC(0–∞), 118 µg·h/mL; C(max), 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD.
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spelling pubmed-49932702016-08-29 Pharmacokinetic profile of defibrotide in patients with renal impairment Tocchetti, Paola Tudone, Elena Marier, Jean-Francois Marbury, Thomas C Zomorodi, Katie Eller, Mark Drug Des Devel Ther Clinical Trial Report Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (C(max)); 108.39 (CI: 97.85, 120.07) for area under the concentration–time curve to the time of the last quantifiable plasma concentration (AUC(0–t)); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC(0–∞)). These ranges were within 80%–125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC(0–t), 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; C(max), 53.8 µg/mL) were within 5%–8% of parameters after the first dose (AUC(0–t), 117 µg·h/mL; AUC(0–∞), 118 µg·h/mL; C(max), 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%–37% and 50%–60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD. Dove Medical Press 2016-08-16 /pmc/articles/PMC4993270/ /pubmed/27574402 http://dx.doi.org/10.2147/DDDT.S112181 Text en © 2016 Tocchetti et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Clinical Trial Report
Tocchetti, Paola
Tudone, Elena
Marier, Jean-Francois
Marbury, Thomas C
Zomorodi, Katie
Eller, Mark
Pharmacokinetic profile of defibrotide in patients with renal impairment
title Pharmacokinetic profile of defibrotide in patients with renal impairment
title_full Pharmacokinetic profile of defibrotide in patients with renal impairment
title_fullStr Pharmacokinetic profile of defibrotide in patients with renal impairment
title_full_unstemmed Pharmacokinetic profile of defibrotide in patients with renal impairment
title_short Pharmacokinetic profile of defibrotide in patients with renal impairment
title_sort pharmacokinetic profile of defibrotide in patients with renal impairment
topic Clinical Trial Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993270/
https://www.ncbi.nlm.nih.gov/pubmed/27574402
http://dx.doi.org/10.2147/DDDT.S112181
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